Eosinophilic syncytial change (ESC), also known as papillary syncytial change, occurs in association with endometrial breakdown and bleeding, especially in nonphysiological conditions. When prominent, this morphological alteration yields a pattern of eosinophilic epithelial cells, often in pseudopapillary arrangements that can mimic cellular changes seen in metaplastic and atypical endometrium. To determine if ESC represents a proliferative, regenerative process or a degenerative, retrogressive alteration, we assessed whether the cells of ESC were actively growing. Our methodology involved a retrospective immunohistochemical study on endometrial biopsies with proliferation markers Ki-67 (MIB-1 antibody) and phosphohistone H3 Ser 28 (pHH3) in 15 cases of multifocal ESC associated with benign endometrium, 5 cases of atypical hyperplasia, and 7 cases of endometrial carcinoma. The Ki-67 proliferative index and the pHH3 mitotic index were calculated per 100 cells for each case. On immunohistochemical analysis, the Ki-67 labeling index was 1.3% for cases of ESC (mean age, 53 yr), 15.8% in atypical hyperplasia (mean age, 51.6 yr), and 42.6% in endometrial carcinoma (mean age, 68.1 yr). In the endometrial cancers, the Ki-67 proliferative index was 10.6% for FIGO grade 1 tumors (n=3), 27.6% for grade 2 tumor (n=1), and 79.6% for serous carcinoma (n=3). The mitotic index calculated from pHH3 immunostaining was zero in all cases of ESC, whereas it was 2.3% in atypical hyperplasia and 4.8% in endometrial carcinomas (2.4% for grade 1, 3% for grade 2, and 7.8% for serous). Our results indicate that ESC is a regressive change. Furthermore, when there is a question of whether eosinophilic endometrial epithelium represents this change, a combination of Ki-67 and pHH3 immunostains can be helpful in distinguishing this entity from more significant processes including carcinoma.